What causes a deranged prothrombin time (PT)?

Causes of Deranged Prothrombin Time

A prolonged PT results from deficiencies in the extrinsic and common coagulation pathways (factors VII, X, V, II, and fibrinogen), with warfarin therapy being the most common cause, followed by liver disease, vitamin K deficiency, and drug interactions. 1

Medication-Related Causes

Warfarin and Vitamin K Antagonists

• Warfarin inhibits vitamin K epoxide reductase, blocking formation of vitamin K-dependent clotting factors (II, VII, IX, and X), which is the most frequent cause of prolonged PT in clinical practice 2, 1
• Drug interactions that inhibit S-warfarin metabolism significantly prolong PT, including phenylbutazone, sulfinpyrazone, metronidazole, trimethoprim-sulfamethoxazole, and amiodarone 2, 1
• Second- and third-generation cephalosporins augment warfarin's anticoagulant effect by inhibiting the cyclic interconversion of vitamin K 2
• Thyroxine increases PT by accelerating metabolism of coagulation factors 2
• High-dose salicylates (≥1.5 g/day) and acetaminophen potentiate warfarin's effect, possibly through warfarin-like activity 2

Antibiotics and Vitamin K Depletion

• Antibiotics commonly cause PT prolongation through vitamin K deficiency, particularly in patients receiving intravenous fluids without vitamin K supplementation 1
• This mechanism is distinct from direct drug interactions and reflects reduced dietary vitamin K intake in sick patients 2

Hepatic Dysfunction

• Hepatic dysfunction prolongs PT through impaired synthesis of coagulation factors, typically requiring loss of >70% of synthetic function to manifest as coagulopathy 1, 3
• Liver disease causes decreased synthesis of factors V, VII, and X, all of which are produced by hepatocytes 3
• Critical pitfall: INR should only be used for warfarin monitoring, not for evaluating PT prolongation from liver disease, as it lacks validity for this indication 1
• In liver disease, activity percentage expression (not INR) provides the most accurate PT reporting across different thromboplastin reagents 4

Vitamin K Deficiency States

Dietary and Malabsorption

• Reduced dietary vitamin K intake potentiates PT prolongation in sick patients treated with antibiotics and intravenous fluids without vitamin K supplementation 2
• Fat malabsorption states reduce vitamin K absorption, leading to deficiency of vitamin K-dependent factors 2

Distinguishing Vitamin K Deficiency from Liver Disease

• In vitamin K deficiency, functional factor II is reduced but factor II antigen and Echis venom-activated factor II remain normal 5
• In liver disease, factor II is reduced by all measurement techniques, reflecting true decreased synthesis rather than impaired activation 5

Congenital Factor Deficiencies

Isolated Factor VII Deficiency

• Isolated factor VII deficiency causes isolated PT prolongation without aPTT abnormality, as factor VII is unique to the extrinsic pathway 1

Factor IX Propeptide Mutation

• A mutation in the factor IX propeptide (present in 1.5% of the population) causes marked factor IX decrease during warfarin therapy with bleeding risk not reflected in PT 2, 1
• This represents a critical diagnostic pitfall: patients with this mutation can bleed despite normal PT/INR values 2

Prothrombin Deficiency

• Prothrombin (factor II) deficiency prolongs both PT and aPTT, as it is part of the common pathway 6
• The hemostatic level of prothrombin is 20-40%, with a half-life of approximately 3 days 6

Hypermetabolic States

• Fever and hyperthyroidism increase PT by accelerating catabolism of vitamin K-dependent coagulation factors 2, 1
• This mechanism is distinct from impaired synthesis and reflects increased turnover of existing factors 2

Laboratory Artifacts and Technical Issues

Pre-analytical Errors

• Underfilling blood collection tubes causes excess citrate and spuriously prolongs PT results—this is a common and preventable error 1, 7
• Using 3.2% citrate collection tubes rather than 3.8% reduces the problem of excess citrate 1

INR Limitations

• INR standardizes PT results only for warfarin monitoring and should not be used for other causes of PT prolongation 1
• INR fails to normalize PT results in liver disease across different thromboplastin reagents 4
• Laboratory-specific ISI verification is essential, as INR values can differ between laboratories even when using identical reagents and coagulometers 8

Combined Pathway Defects

• Combined PT and aPTT prolongation suggests common pathway defects (factors X, V, II, fibrinogen) or multiple factor deficiencies 1
• This pattern requires evaluation for disseminated intravascular coagulation, severe liver disease, or combined factor deficiencies 1

Patient-Specific Risk Factors

Age-Related Changes

• Elderly patients show exaggerated warfarin response due to reduced drug clearance with age 2, 1

Hereditary Warfarin Resistance

• Hereditary warfarin resistance is rare but requires 5- to 20-fold higher doses than average due to reduced affinity of warfarin for its hepatic receptor 2, 1

Critical Clinical Considerations

• PT may be only modestly prolonged in severe illness; subtle elevations can still indicate significant coagulopathy 1
• Dietary vitamin K fluctuations significantly affect warfarin response, with green vegetables and supplements counteracting anticoagulation 2
• Heparin potentiates warfarin's anticoagulant effect but produces only slight PT prolongation in therapeutic doses 2